Since current methods to predict the efficacy or toxicity of new drug candidates in humans are often inaccurate, can we develop new methods to test potential therapeutic agents that yield better predictions of response? Provocative questions demand bold answers. Here we propose a radically new bioengineering approach to drug screening that employs arrayed human 3D microtumors, supported by perfused capillaries. Tumor cells grow within a small chamber filled with complex ECM and stromal cells, and are nourished by a network of newly-formed capillaries that are connected to an artificial arteriovenous system. Hundreds of chambers can be arranged on a single chip, each with its own vascular supply, thereby allowing for development of a high- throughput screening (HTS) platform. Tumor lines can be used for drug-discovery, or patient-specific tumor cells for personalized screening. This system combines the advantages of tissue culture - defined, rapid, cost- effective and reproducible - with the advantages of mouse models - 3-dimensional, multiple cell types interacting, complex pharmacodynamics, and dependence on vasculature for survival and drug-delivery. In addition, lentiviral-mediated expression of red, yellow and green fluorescent proteins in the tumor cells, endothelial cells and stromal cells will allow for repeate, rapid and quantitative assessment of drug toxicity/efficacy against each cell type over time. Importantly, the key technologies underlying this proposal have already passed the proof-of-concept stage - we now seek to optimize and harmonize the components into a working HTS platform that will more accurately predict how drugs will act in humans.